Genetic mechanisms of arterial stiffness in polygenic salt-sensitive hypertension

描述(由申请人提供)：我们的长期目标是阐明原发性或多基因高血压的病因学，重点是阐明高血压易感性的遗传变异以及加剧高血压易感性和终末器官疾病的基因-环境相互作用。在临床研究中，以脉搏波速度或脉搏波速度(PWV)衡量动脉硬化的重要性日益显现，这些研究表明脉搏波速度增加与心血管结局(中风、冠心病和慢性肾脏病)之间存在关联，这可能是一个可靠的预测参数，但同时也强调了动物模型研究解决机制的必要性。因此，这项研究计划集中于RFA所述的目标：#1)“在动物模型中探索动脉硬化和高血压发展之间的时间关系”，以及#2)“在(原发性/多基因)高血压的背景下，对导致导管动脉硬化的机制进行细胞和分子研究”。为了实现这一目标，我们优先考虑了以下具体目标：目的1.研究大动脉硬化(通过高分辨率超声测量主动脉PWV和应变，颈动脉PWV和应变)与盐敏感型高血压(通过对SBP、DBP、MAP和PP的无应激24/7遥测血压分析测量)和卒中的发生之间的时间关系。目的2.明确动脉和颈动脉三层结构在时间和空间上的变化，以及在高血压及其终末器官并发症的病程中，钠诱导的动脉僵硬加重和进展所可能存在的基因表达变化。目的3.通过对F_2代[S×R]互交雄性和雌性大鼠的全基因组扫描，单独或交互作用地识别共同的和性别特异的数量性状基因座，阐明遗传机制在多基因盐敏感型高血压背景下动脉僵硬的原因中所起的作用。总之，这三个目标将阐明在钠诱导的卒中倾向高血压大鼠模型中，主动脉和颈动脉僵硬与多基因(本质)高血压和卒中的关系，以及对病因的细胞、分子和遗传机制的洞察。

DESCRIPTION (provided by applicant): Our long term goal is to elucidate the etiology of essential or polygenic hypertension with a focus on the elucidation of genetic variants that underlie hypertension susceptibility and gene-environment interactions which exacerbate hypertension susceptibility and end-organ disease. The emerging importance of arterial stiffening measured as pulse wave velocity or PWV in clinical studies demonstrating the association of increased PWV and cardiovascular outcomes (stroke, coronary heart disease, and chronic kidney disease) has pinpointed a likely robust predictive parameter, but at the same time highlighted the need for animal model studies to address mechanisms. Accordingly, this research proposal focuses on RFA-stated goals: #1) "to explore the temporal relationship between arterial stiffening and the development of hypertension in an animal model", and #2) to conduct "cellular and molecular investigation of mechanisms that lead to conduit artery stiffening in the context of (essential/polygenic) hypertension". To accomplish this we have prioritized the following specific aims: Aim 1. Examine the temporal relation between large artery stiffening (measured as aortic PWV and strain, carotid PWV and strain via high-resolution ultrasonography), and the development of salt-sensitive hypertension (measured via non-stress 24/7 telemetric BP analysis of SBP, DBP, MAP and PP) and stroke in both male and female stroke-prone Dahl S rats. Aim 2. Define the temporal and spatial changes in aortic and carotid artery structure in all three vessel layers, along with putative gene expression changes that underlie Na-induced exacerbation and progression of arterial stiffness along the disease course of hypertension and its end-organ complications. Aim 3. Elucidate the role of genetic mechanisms in the causation of arterial stiffness in the context of polygenic salt-sensitive hypertension via genome-wide scan of F2[Dahl S x Dahl R]-intercross male and female rats identifying common and sex-specific quantitative trait loci (QTLs) that contribute to arterial stiffness individually or interactively. Altogether, these three aims will elucidate the relationship of aortic and carotid arterial stiffness to polygenic (essential) hypertension and stroke in a Na-induced stroke-prone hypertension rat model, as well as give insight into causal cellular, molecular, and genetic mechanisms.